EP0098204A1 - Compositions thérapeutiques à base d'hydrazones N-substituées et nouvelles hydrazones N-substituées - Google Patents

Compositions thérapeutiques à base d'hydrazones N-substituées et nouvelles hydrazones N-substituées Download PDF

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Publication number
EP0098204A1
EP0098204A1 EP83401266A EP83401266A EP0098204A1 EP 0098204 A1 EP0098204 A1 EP 0098204A1 EP 83401266 A EP83401266 A EP 83401266A EP 83401266 A EP83401266 A EP 83401266A EP 0098204 A1 EP0098204 A1 EP 0098204A1
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EP
European Patent Office
Prior art keywords
group
alkyl
formula
carboxy
nitrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP83401266A
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German (de)
English (en)
French (fr)
Inventor
Claude Coquelet
Chantal Résidence"Le Languedoc"Bât. A4 Bertez
Claude Bonne
Daniel Syncholle
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Laboratoires Chauvin SAS
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Laboratoires Chauvin Blache SA
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Publication date
Application filed by Laboratoires Chauvin Blache SA filed Critical Laboratoires Chauvin Blache SA
Publication of EP0098204A1 publication Critical patent/EP0098204A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new therapeutic compositions containing, as active ingredient, N-substituted hydrazones. These compositions can be used in the treatment of inflammatory phenomena and in particular in the treatment of ocular inflammatory phenomena.
  • the ocular inflammatory response is se- q uence of events caused by injury or irritation to the eye tissue. It results in increased intraocular pressure, leukocyte infiltration in the tissues and fluids of the eye, an increase in the level of proteins in the aqueous humor and uveitis.
  • the simultaneous inhibition of the 5-lipoxygenase and cyclooxygenase pathway is capable of blocking the synthesis of the various pro-inflammatory mediators as do glucocorticolles but without exhibiting the annoying effects.
  • the present invention is precisely based on the discovery that certain hydrazones inhibit both leukocyte lipoxygenase and the formation of platelet prostanoids. They therefore oppose the development of the vascular phase of inflammation (involving HETE s ).
  • addition salts with pharmaceutically acceptable acids denotes the salts which have the biological properties of the free bases, without having any undesirable effect.
  • These salts can in particular be those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acidic metal salts such as disodium orthophosphate and monopotassium sulfate, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, citric acid, malic acid , methane sulfonic acid, lactic acid, succinic acid, tartaric acid and pamoic acid.
  • halogen refers to chlorine, bromine or iodine.
  • bi- or polycyclic aromatic hydrocarbon radicals is meant bi- or polycyclic radicals having at least one aromatic ring.
  • non-aromatic mono- or polycyclic hydrocarbon radicals is meant cyclic hydrocarbon radicals having no aromatic ring.
  • bi- or polycyclic heteroaromatic radicals is meant bi- or polycyclic radicals having at least one aromatic ring.
  • examples of such radicals include chromannylidene, chromennylidene, phenylchromannylidene and indinylylidene radicals.
  • non-aromatic nitrogen heterocyclic groups falling within the definition of R 3
  • non-aromatic heterocyclic groups falling within the definition of -NR 4 R 5
  • heteroaromatic groups falling within the definition of R 2 , mention may be made of thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, isoxazolyl groups.
  • the new compounds and the known compounds can be obtained by conventional methods.
  • the compounds of formula (I) in which R 1 is a hydrogen atom, an alkyl or cycloalkyl group can be prepared by reaction of a hydrazine of formula on a ketone of formula R 1 and R 2 having the definition given above.
  • the reaction can be carried out in particular in solution in an alcohol, in the presence of a catalytic amount of an acid such as acetic acid or hydrochloric acid.
  • the reaction is generally carried out at elevated temperature, advantageously at the reflux temperature of the solvent, using equimolar amounts of hydrazine II and ketone III and for a period of 15 min to 3 hours.
  • the reaction can be carried out by heating. at reflux of equimolar amounts of hydrazine II and ketone III in a 10% aqueous solution of acetic acid for 1 to 3 hours.
  • Hydrazine II can also be reacted with ketone III by adding to the ketone III in solution in an alcohol an equimolar amount of 2-thiazolyl hydrochloride hydrazine in aqueous solution. The reaction takes place at room temperature and can be obtained for example by stirring for 15 min.
  • the hydrazones of formula I in which R 1 represents a hydroxy group can be prepared by reaction of hydrazine II in solution in pyridine with an equimolar amount of acid chloride of formula
  • the reaction can be carried out at 5 ° C with stirring.
  • the compounds of formula (I) in which R 1 is an alkoxy group can be obtained from the compounds of formula (I) in which R 1 is a hydroxy group, according to conventional etherification methods.
  • R 1 is a group -NHR 3 or -NR 4 R S
  • R S can be obtained from a hydrazonic acid chloride of formula by addition of an amine -NH 2 R 3 or -NHR 4 R 5 .
  • the compounds of formula (I) in which Z is a thiazolyl-2 group can also be prepared by reaction of a ketone III with the thiosemi-carbazide and reaction of the thiosemicarbazone obtained with 1,2-dichloro-2-ethoxy-ethane, chloroacetaldehyde, chloroacetaldehyde diethylacetal or 1,2-dichloroethyl acetate, according to the following scheme:
  • thiosemicarbazone V with for example chloroacetaldehyde diethylacetal can be carried out by bringing to reflux for one hour an alcoholic solution of equimolar amounts of the reactants.
  • the addition salts with pharmaceutically acceptable acids can be prepared in a conventional manner by reaction of the free bases with an acid or a salt, in particular in solution in an alcohol.
  • Table Ia gives examples of compounds of formula and Table Ib gives examples of compounds of formula
  • Rabbit peritoneal leukocytes are obtained and prepared according to the technique described by P. Borgeat and B. Samuelson (J. Biol. Chem. 254, n ° 8, p.2643, 1979).
  • Fig. 2a shows a characteristic chromatographic profile of the metabolism of 14 C-AA in PMN s peritoneal rabbit compared to that obtained in the presence of the compound of Example 3b (50 ⁇ M) (Fig. 2b). This last line highlights the inhibition of the metabolism of the 5-lipoxygenase pathway.
  • the percentage inhibition of the 5-lipoxygenase pathway is measured as a function of the concentration of each compound. From these curves, we deduce the concentration of product inhibiting 50% of metabolism (IC50).
  • the platelet suspension (0.4 ml / tube) is preincubated for 15 minutes at 37 ° C, either with 10 ⁇ l of DMSO (control), or with various concentrations of products to be treated in solution in 10 ⁇ l of DMSO.
  • the incubation is carried out in the presence of 14 C-Arachidonate (1 ⁇ g, 0.2 ⁇ Ci) distributed in 0.1 ml of Buffer II. It is blocked after 15 minutes with 50 ⁇ l of citric acid and 250 ⁇ l of saturated NaCl.
  • Figs. 3a and 4a give the chromatographic profiles of the metabolism of 14 C-AA in rabbit platelets, compared with that obtained in the presence of Aspirin (Fig. 3b) and of the compound of Example 3b (Fig. 4b).
  • the percentage inhibition of the pathways of prostanoids and of 12-lipoxygenase is estimated by measuring the disappearance of 12-HETE and of thromboxane B 2 (TxB 2 ) as a function of various concentrations of each compound.
  • the effect of the various concentrations of each compound is measured on at least seven rats.
  • mice used are of Swiss strain (NMRI-Han).
  • the average weight of male animals is 30 g, that of females 25 g.
  • the compounds in solution in DMSO are injected under the ventral side of the peritoneum, in increasing doses.
  • the control batch receives DMSO under the same conditions (2.5 ml.kg -1 ).
  • the LD 50 is determined after 14 days of observation.
  • Table III gives the values 50% lethal doses accompanied by the 5% confidence interval.
  • compositions according to the invention can be administered to humans or to animals by topical, oral or parenteral route (including intraarticular route).
  • They can be in the form of solid, semi-solid or liquid preparations.
  • compositions the active principle is generally mixed with one or more usual pharmaceutically acceptable excipients well known to those skilled in the art.
  • compositions which can be administered topically may contain in particular from 0.5 to 5% by weight of active principle.
  • compositions which can be administered orally or parenterally can in particular contain from 1 to 60% by weight of active principle.
  • the amount of active ingredient administered obviously depends on the patient being treated, the route administration and severity of the disease. However for administration by the oral or parenteral route, about 0.25 to 5 mg / kg / day can be administered, that is to say in a 70 kg man from 17.5 to 350 mg / kg / day and, preferably , from 25 to 250 mg / day.
  • the compounds of formula I and their addition salts with pharmaceutically acceptable acids can also be used because of their antioxidant properties as preservatives and antioxidants in human and animal food.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP83401266A 1982-06-18 1983-06-17 Compositions thérapeutiques à base d'hydrazones N-substituées et nouvelles hydrazones N-substituées Withdrawn EP0098204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8210687A FR2528844A1 (fr) 1982-06-18 1982-06-18 Nouvelles thiazolyl-2 hydrazones, leur procede de preparation et leur application en therapeutique
FR8210687 1982-06-18

Publications (1)

Publication Number Publication Date
EP0098204A1 true EP0098204A1 (fr) 1984-01-11

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EP83401266A Withdrawn EP0098204A1 (fr) 1982-06-18 1983-06-17 Compositions thérapeutiques à base d'hydrazones N-substituées et nouvelles hydrazones N-substituées

Country Status (6)

Country Link
US (1) US4656184A (enrdf_load_stackoverflow)
EP (1) EP0098204A1 (enrdf_load_stackoverflow)
JP (1) JPS59501111A (enrdf_load_stackoverflow)
CA (1) CA1231342A (enrdf_load_stackoverflow)
FR (1) FR2528844A1 (enrdf_load_stackoverflow)
WO (1) WO1984000007A1 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019335A1 (en) * 1993-02-26 1994-09-01 Otsuka Pharmaceutical Co., Ltd. Thiazole or imidazole derivatives as maillard reaction inhibitors
WO1992019572A3 (de) * 1991-05-04 1996-09-19 Lettau Gudrun & Hf 1-aza-2-phenylhydrorazino-heterocyclen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166163A (en) * 1990-09-10 1992-11-24 Hoechst-Roussel Pharmaceuticals Incorporated 3-(1H-indazol-3-yl)-4-pyridinamines
CA2469709A1 (en) * 2001-12-10 2003-06-19 Temple University - Of The Commonwealth System Of Higher Education Substituted hydrazones as inhibitors of cyclooxygenase-2

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2105698A5 (enrdf_load_stackoverflow) * 1970-09-17 1972-04-28 Roussel Uclaf

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2105698A5 (enrdf_load_stackoverflow) * 1970-09-17 1972-04-28 Roussel Uclaf

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, no. 9-10, septembre-octobre 1973, pages 2843-2847, Paris, FR. *
CHEMICAL ABSTRACTS, vol. 73, no. 16, 19 octobre 1970, page 66, no. 78537g, Columbus, Ohio, USA & JP-B1-45 012594 (NIPPON KAYAKU CO., LTD.) 07-05-1970 *
CHEMISCHE BERICHTE, vol. 85, no. 12, 1952, pages 1122-1129, Weinheim, DE. *
CHEMISCHE BERICHTE, vol. 89, no. 5, mai 1956, pages 1095-1099, Weinheim, DE. *
TALANTA, vol. 27, no. 1, 1980, pages 55-58, Pergamon Press Ltd., Oxford, GB. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019572A3 (de) * 1991-05-04 1996-09-19 Lettau Gudrun & Hf 1-aza-2-phenylhydrorazino-heterocyclen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
WO1994019335A1 (en) * 1993-02-26 1994-09-01 Otsuka Pharmaceutical Co., Ltd. Thiazole or imidazole derivatives as maillard reaction inhibitors

Also Published As

Publication number Publication date
FR2528844A1 (fr) 1983-12-23
FR2528844B1 (enrdf_load_stackoverflow) 1985-03-22
JPS59501111A (ja) 1984-06-28
WO1984000007A1 (fr) 1984-01-05
CA1231342A (fr) 1988-01-12
US4656184A (en) 1987-04-07

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Inventor name: COQUELET, CLAUDE

Inventor name: SYNCHOLLE, DANIEL

Inventor name: BONNE, CLAUDE

Inventor name: BERTEZ, CHANTALRESIDENCE"LE LANGUEDOC"BAT. A4